Adenosine can be considered to be a hormone which has been shown to have a number of significant effects on the mammalian central nervous system [Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; International Review of Neurobiology (Smythies, J. R. and Bradley, R. J., eds.) Academic Press Inc., 1985.27, 63-139], especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31,85-108, Trends in Pharmacological Sciences, 1983, 9, 193-194). For example, the concentration of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or ccnditions of neuronal ischaemia/anoxia (Brain Research 1990, 516, 248-256).
It has been established for some years now that centrally acting adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity. Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) (Nature, 1985, 316, 148-150, Journal of Neurochemistry, 1992, 58, 1683-1689).
There are several CNS ailments for which this adenosine receptor mediated neuromodulator activity could be of clear therapeutic benefit. Examples of these would include the treatment of convulsive disorders (European Journal of Pharmacology, 1991, 195, 261-265; Journal of Pharmacology and Experimental Therapeutics, 1982, 220, 70-76), prevention of neurodegeneration under conditions of brain anoxia/ischaemia (Neuroscience Letters, 1987, 83, 287-293; Neuroscience, 1989, 30, 451-462; Pharmacology of Cerebral Ischaemia 1990 (Kriegelstein, J. and Oberpichler, H., Eds., Wissenschaftliche Verlagsgesellschaft mbH: Stuttgart, 1990, pp 439-448) or the use of a purinergic agent in the treatment of pain (European Journal of Pharmacology, 1989, 162, 365-369; Neuroscience Letters, 1991, 121, 267-270). In addition, the antiischaemic effect of the compounds described within this invention may be useful in protecting against cardiac ischaemia.
Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into two distinct receptor types which have become known as A1 and A2. Extensive research has been carried out in a quest to identify selective ligands at these sites [see, for example, Comprehensive Medicinal Chemistry Volume 3, (Hansch, C., Sammes, P. G. and Taylor, J. B., Eds., Pergamon Press PLC: 1990, pp 601-642)]. Selective ligands exist for A1 and A2 adenosine receptors and the structure-activity relationships of the various reference ligands have been reviewed (Biochemical Pharmacology, 1986, 35, 2467-2481) together with their therapeutic potential (Journal of Medicinal Chemistry, 1992, 35, 407-422). Among the known adenosine receptor agonists most selective for the A1 receptor over the A2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyl group on the amino function, for example N-cyclopentyladenosine and N-cyclohexyladenosine (Journal of Medicinal Chemistry, 1985, 28, 1383-1384) or 2-chloro-N-cyclopentyladenosine (Naunyn-Schmiedeberg's Arch pharmacal. 1988, 337, 687-689).
Examples of adenosine derivatives in the chemical literature with the heteroatoms, oxygen or nitrogen bonded directly to the 6-amino substituent are summarised below.
Examples with hydrogen at the purine 2-position include N-aminoadenosine, N-[(N-methyl-N-phenyl)amino]adenosine, N-hydroxyadenosine, N-methoxyadenosine and N-benzyloxyadenosine (Journal of Medicinal Chemistry, 1985, 28, 1636-1643); N-ethoxyadenosine (Chemical and Pharmaceutical Bulletin, 1973, 21, 1676-1682; ibid., 1973, 21, 1835-1838); N-(methylamino)adenosine and N-[(N-hydroxy-N-methyl)amino]adenosine (Journal of Medicinal Chemistry, 1968, 11, 521-523).
Examples of adenosine derivatives with oxygen or nitrogen atoms bonded to the 6-amino substituent, containing an additional purine 2-substituent are 2-amino-N-hydroxyadenosine (Journal of Medicinal Chemistry, 1972, 15, 387-390); 2-amino-N-aminoadenosine (Chemical and Pharmaceutical Bulletin, 1969, 17, 2373-2376); 2-amino-N-methoxyadenosine (Chemical and Pharmaceutical Bulletin, 1975, 23, 464-466); 2-chloro-N-hydroxyadenosine (Journal of Medicinal Chemistry, 1991, 34, 2226-2230), 2-fluoro-N-aminoadenosine (Journal of Medicinal Chemistry, 1970, 13, 427-430) and 2-fluoro-N-hydroxyadenosine (Journal of Medicinal Chemistry, 1971, 14, 816-819).
In the above scientific articles, no mention is made of any pharmacological effects of the compounds concerned on the central nervous system.
In U.S. Pat. No. 3,819,613, substituted adenosine analogues with hydrazone derivatives on the 6-amino function are disclosed as hypotensive agents. In GB 1,351,501, adenosine and 2-aminoadenosine derivatives having a --NH--R.sub.2 group joined to the 6-amino function are disclosed as coronary dilators and platelet aggregation inhibitors. In EP A 152,944, a series of 2-, 6- and 8-substituted adenosine derivatives are described having activity as anti-allergy agents. In EP A 253,962, adenosine and 2-haloadenosine analogues having an alkyl, cycloalkyl or an aralkyl group attached to the 6-amino function are described with activity as anti-dementia agents. In EP 402,752A, derivatives of adenosine unsubstituted in the 2-position are described which have a substituted heteroaromatic 1-pyrrolyl moiety attached to the 6-amino group. In WO 91/04032, methods of preventing neural tissue damage in neurodegenerative diseases by increasing extracellular concentrations of adenosine are described. Examples are given of prodrug esters of AICA riboside (5-amino-1-.beta.-D-ribofuranosyl)imidazo-4-carboxamide) which are claimed to be centrally acting neuroprotective agents. In WO 92/02214, analogs of AICA riboside are revealed for the treatment of myocardial and cerebral ischaemias. In WO 90/05526, 2-(alkylalkynyl)adenosine derivatives are described for treatment of ischaemic disease of the heart and brain.
The present invention relates to new adenosine analogues having potent binding in vitro to the adenosine A1 receptor, and at the same time showing selectivity for A 1 receptor binding in vitro over that to the A2 receptor subtype. In addition, many of the novel compounds contained in this invention have a relatively high lipophilicity, especially when compared to adenosine analogues and adenosine itself which are not substituted on the 6-amino group or the purine 2-position. This latter property may make these compounds suitable for passage across the blood brain barrier.
The possibility that some of the compounds may be substrates for nucleoside-specific active transport systems into the CNS across the blood barrier is, however, not excluded. These useful properties support the notion that some of the examples may have potential as candidate drugs for treatment of the CNS ailments mentioned within this invention in humans.
The compounds of the invention are purine derivatives of formula I, or a pharmaceutically acceptable salt thereof: ##STR2## wherein
X represents hydrogen, halogen, amino, perhalomethyl, acetamido, cyano, C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, C.sub.1-6 -alkylthio or C.sub.1-6 -alkylamino;
R.sup.1 is --NR.sup.2 R.sup.3, --YR.sup.4,
wherein Y is oxygen or sulphur;
R.sup.2 is C.sub.1-6 alkyl;
R.sup.3 is phenyl or C.sub.1-6 -alkyl, which may be substituted with phenyl or phenoxy;
R.sup.4 is naphthyl;
partly saturated naphthyl;
C.sub.1-6 -alkyl, which may be substituted with phenoxy or phenyl, which may be substituted with nitro, halogen or amino;
or C.sub.3-8 -cycloalkyl, which may be substituted with phenyl or phenoxy;
In certain examples, the group R.sup.1 can contain one or more asymmetric carbon atoms in addition to those asymmetric centres already present in the molecule. In examples where this is the case, this invention includes all resulting diastereoisomers and mixtures thereof.
Various salts of compounds of formula (I) can be prepared which can be considered physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutarates, glutaconates, lactates, maleates, methanesulphonates, phosphates, salicylates, succinates, sulphates, sulphamates, tartrates and paratoluenesulphonates. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
Compounds of formula (I), which act as adenosine receptor agonists, are found to be useful in the treatment of central nervous system conditions such as anxiety, neuronal ischaemia/anoxia, convulsive disorders (epilepsy) and neurodegeneration (including Parkinson's disease).
Further, the compounds of formula (I) are found to be useful as analgesic agents, in lowering plasma free fatty acid (FFA) levels or as cardiovascular agents and also have application to myocardial ischaemia.
The invention also relates to methods of preparing the above mentioned compounds. These methods comprise: